A genomic variant of ALPK2 is associated with increased liver fibrosis risk in HIV/HCV coinfected women.

HIV coinfection is associated with more rapid liver fibrosis progression in hepatitis C (HCV) infection. Recently, much work has been done to improve outcomes of liver disease and to identify targets for pharmacological intervention in coinfected patients. In this study, we analyzed clinical data of 1,858 participants from the Women's Interagency HIV Study (WIHS) to characterize risk factors associated with changes in the APRI and FIB-4 surrogate measurements for advanced fibrosis. We assessed 887 non-synonymous single nucleotide variants (nsSNV) in a subset of 661 coinfected participants for genetic associations with changes in liver fibrosis risk. The variants utilized produced amino acid substitutions that either altered an N-linked glycosylation (NxS/T) sequon or mapped to a gene related to glycosylation processes. Seven variants were associated with an increased likelihood of liver fibrosis. The most common variant, ALPK2 rs3809973, was associated with liver fibrosis in HIV/HCV coinfected patients; individuals homozygous for the rare C allele displayed elevated APRI (0.61, 95% CI, 0.334 to 0.875) and FIB-4 (0.74, 95% CI, 0.336 to 1.144) relative to those coinfected women without the variant. Although warranting replication, ALPK2 rs3809973 may show utility to detect individuals at increased risk for liver disease progression.

Clinical Performance of the BD CTGCTV2 Assay for the BD MAX System for Detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis Infections.

BACKGROUND: Diagnostic options to combat the increasing rates of sexually transmitted infections recorded throughout the world increasingly include multiplex assays. Here we describe the estimated sensitivity and specificity of a triplex molecular assay that simultaneously detects Chlamydia trachomatis (CT), Neisseria gonorrhoeae (or gonococci [GC]), and Trichomonas vaginalis (TV). METHODS: Participants (2547 women and 1159 men) were recruited from 12 clinics in the United States. BD CTGCTV2 for BD MAX System assay (CTGCTV2) results were obtained from vaginal and endocervical swabs, endocervical samples in cytology medium, and female and male urine. Results were compared with infection standards that were sample type and pathogen dependent. RESULTS: Female specimen sensitivity estimates ranged from 92.7% to 98.4%, 92.9% to 100%, and 86.6% to 100% for CT, GC and TV, respectively. Male urine sensitivity estimates were 96.7%, 99.2%, and 97.9% for CT, GC, and TV, respectively. Specificity estimates were >98.7% for all sample types. CONCLUSIONS: BD CTGCTV2 performed well using a variety of sample types. As a true triplex assay, performed using a benchtop instrument, BD CTGCTV2 may be useful in settings where no testing is currently performed and in settings, such as reference laboratories, where testing turnaround time may be several days. Use of this assay at local laboratories may result in greater access to testing and a shorter time to result, which are important steps for improving our ability to combat sexually transmitted infections.

Loss of Preexisting Immunological Memory Among Human Immunodeficiency Virus-Infected Women Despite Immune Reconstitution With Antiretroviral Therapy.

BACKGROUND: It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections. METHODS: We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA). RESULTS: There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24-108 years; P = .001). CONCLUSIONS: Despite antiretroviral therapy-associated improvement in CD4+ T-cell counts (nadir, <200/µL; >350/µL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.

Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients.

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%-94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Estimating past hepatitis C infection risk from reported risk factor histories: implications for imputing age of infection and modeling fibrosis progression.

BACKGROUND: Chronic hepatitis C virus infection is prevalent and often causes hepatic fibrosis, which can progress to cirrhosis and cause liver cancer or liver failure. Study of fibrosis progression often relies on imputing the time of infection, often as the reported age of first injection drug use. We sought to examine the accuracy of such imputation and implications for modeling factors that influence progression rates. METHODS: We analyzed cross-sectional data on hepatitis C antibody status and reported risk factor histories from two large studies, the Women's Interagency HIV Study and the Urban Health Study, using modern survival analysis methods for current status data to model past infection risk year by year. We compared fitted distributions of past infection risk to reported age of first injection drug use. RESULTS: Although injection drug use appeared to be a very strong risk factor, models for both studies showed that many subjects had considerable probability of having been infected substantially before or after their reported age of first injection drug use. Persons reporting younger age of first injection drug use were more likely to have been infected after, and persons reporting older age of first injection drug use were more likely to have been infected before. CONCLUSION: In cross-sectional studies of fibrosis progression where date of HCV infection is estimated from risk factor histories, modern methods such as multiple imputation should be used to account for the substantial uncertainty about when infection occurred. The models presented here can provide the inputs needed by such methods. Using reported age of first injection drug use as the time of infection in studies of fibrosis progression is likely to produce a spuriously strong association of younger age of infection with slower rate of progression.

Treatment of syphilis 2001: nonpregnant adults.

After a precipitous increase in the incidence of infectious syphilis in the United States during the late 1980s and early 1990s, the rate of new cases has declined so dramatically that a program initiated by the Centers for Disease Control and Prevention (CDC) to achieve elimination appears to stand a good chance of succeeding. In the fall of 2000, the CDC convened an advisory group to examine the recent medical literature regarding syphilis treatment. Published literature in peer-reviewed journals and abstracts from relevant scientific meetings that have appeared since the last STD Treatment Guidelines meeting in 1997 were reviewed. Where applicable, unpublished data from studies in progress were also discussed. Expert opinion was sought. Through all these efforts, it appears that the azalide azithromycin and the third-generation cephalosporin ceftriaxone should find more definitive roles in the treatment of syphilis. None will eclipse the continued primacy of penicillin for this purpose.